The diverse family of isoprenoid lipids, of which the retinoids represent one class, has been used in cellular signaling pathways since the beginning of multicellular life. Processes in vertebrates as diverse as growth, vision, and reproduction are "retinoid" dependent. The Retinoids, Vol. 2, eds. Spom, M. B., Roberts, A. B., & Goodman, D. S., pp. 289-286 Academic, Orlando 1984!. Retinoids are a group of compounds consisting of retinol (i.e. Vitamin A) and natural and synthetic derivatives thereof.
Various metabolic derivatives of retinol have been identified. Retinoic acid has been found to be crucial for normal pattern formation during embryogenesis and in the regulation of the differentiation of a variety of cell types (Gudas L. J., J. Biol. Chem., 2679:15399-402 (1994)) , 11-cis retinal in vision (Wald, G. , Science, 162:230-32 (1968)) or 9-cis and all-trans retinoic acid for differentiation of a number of cellular systems (The Retinoids, Vol. 2, eds. Sporn, M. B., Roberts, A. B., & Goodman, D. S., pp. 289-286 Academic, Orlando 1984!).
Furthermore, retinoic acid receptors are members of an ancient superfamily of nuclear receptors, some of which respond to other isoprenoid derivatives, e.g. steroids (Evans, R. M., Science, 240:889-95 (1988) and Green et al., Trends, in Genet., 4:309-14 (1988)), vitamin D (McDonnell et al., Science, 235:1214-17 (1987)) and ecdysone (Koelle et al., Cell, 67:59-77 (1991)).
The general mechanism of action of retinoids presumably is connected with their specific binding proteins including nuclear receptor molecules that are involved in transcriptional regulation (Evans, R. M., Science, 240:889-95 (1985) and Green et al., Trends in Genet., 4:309-14 (1988)). Retro-retinoids are characterized by a planar ring-to-tail configuration, rigidly enforced by the rearrangement of the carbon double bond system to fix the hexenyl ring by a double bond to the polyene tail. The first of the natural retro-retinoids to be discovered, 14-hydroxy-4,14-retro-retinol ("14-HRR") plays a role in the regulation of lymphocyte proliferation. Garbe et al., J. Exp. Med., 176:109-17 (1992) and Buck et al., Science, 254:1654-56 (1991).
The hydrocarbon anhydroretinol, first detected in 1939 in fish liver oils (Embree, N. D., J. Biol Chem., 128:187-198 (1939)), is structurally related to 14-HRR and was, therefore, tested for its effects on B cell proliferation. B lymphocytes, although retinol-dependent, do not use retinoic acid as mediator. Retinol is metabolized by B lymphocytes and other cell lines to optically active 14-HRR. It is this compound that mediates the growth control. Buck et al., Science, 254:1654-56 (1991).
Anhydroretinol, although a structural analog of 14-HRR, has been shown to be an antagonist to 14-HRR and not an aid to B cell proliferation. However, it reversibly inhibits retinol- and 14-HRR-dependent effects and blocks B lymphocyte proliferation as well as activation of resting T lymphocytes. Buck et al., J Exp. Med., 178:675-80 (1993).
It has been shown that spontaneously transformed mouse fibroblasts (Balb/c 3T12-13 cells) cultured in vitro in the presence of trans retinol synthesized the hydrocarbon anhydroretinol and metabolite-310 from retinol. Moreover, incubation of metabolite-310 with the 3T12 microsomes yielded anhydroretinol by these cells, suggesting that metabolite-310 is an intermediate in the synthesis of anhydroretinol by these cells i.e., retinol is enzymatically converted to anhydroretinol. Bhat et al., J. Lipid Res., 20:357-62 (1979). Furthermore, anhydroretinol's antagonism to 14-HHR suggests that this retro-retinoid might function as a ligand for cytoplasmic or nuclear receptors. Derguini et al., Angew. Chem. Int. Ed. Engl., 33(18):1837-39 (1994).
WO 94/20081 to Hammerling et al. discloses anhydroretinol and derivatives thereof, for inhibiting the growth of cells, treating a subject having a disease characterized by an uncontrolled growth of cells, and blocking an immune response.